Bioran (Tablets, Solution, Gel) Instructions for Use

ATC Code

M01AB05 (Diclofenac)

Active Substance

Diclofenac

Clinical-Pharmacological Group

NSAID

Pharmacotherapeutic Group

NSAID

Pharmacological Action

NSAID, a phenylacetic acid derivative. It has a pronounced anti-inflammatory, analgesic, and moderate antipyretic effect.

The mechanism of action is associated with the inhibition of COX activity, the key enzyme in the metabolism of arachidonic acid, which is a precursor of prostaglandins that play an important role in the pathogenesis of inflammation, pain, and fever.

The analgesic effect is due to two mechanisms: peripheral (indirectly, through suppression of prostaglandin synthesis) and central (due to inhibition of prostaglandin synthesis in the central and peripheral nervous system).

In vitro, at concentrations equivalent to those achieved in the treatment of patients, it does not inhibit the biosynthesis of proteoglycans in cartilage tissue.

In rheumatic diseases, it reduces joint pain at rest and during movement, as well as morning stiffness and joint swelling, and helps to increase the range of motion.

It reduces post-traumatic and postoperative pain, as well as inflammatory edema.

In post-traumatic and postoperative inflammatory conditions, it quickly relieves pain (occurring both at rest and during movement) and reduces inflammatory edema and postoperative wound edema.

It inhibits platelet aggregation. With long-term use, it has a desensitizing effect.

Pharmacokinetics

After intramuscular injection of diclofenac at a dose of 75 mg, its absorption begins immediately.

The C_max in plasma is on average about 2.5 µg/ml (8 µmol/l) and is reached in approximately 20 minutes.

The amount of the absorbed active substance is linearly dependent on the administered dose.

The AUC after intramuscular injection of diclofenac is approximately 2 times greater than after its oral or rectal administration, since in the latter cases about half of the amount of diclofenac is metabolized during the “first pass” through the liver.

With subsequent administrations, the pharmacokinetic parameters do not change.

Provided that the recommended intervals between diclofenac injections are observed, no accumulation is noted.

Plasma protein binding is 99.7%, mainly with albumin (99.4%). The apparent V_d is 0.12-0.17 l/kg.

Diclofenac penetrates into the synovial fluid, where its C_max is reached 2-4 hours later than in the blood plasma.

The apparent T_1/2 from the synovial fluid is 3-6 hours.

2 hours after reaching C_max in the blood plasma, the concentration of diclofenac in the synovial fluid is higher than in the blood plasma, and its values remain higher for a period of up to 12 hours.

Diclofenac was detected in low concentrations (100 ng/ml) in the breast milk of one of the nursing mothers.

The estimated amount of the drug entering the child’s body through breast milk is equivalent to 0.03 mg/kg/day.

The metabolism of diclofenac occurs partially by glucuronidation of the unchanged molecule, but predominantly through single and multiple hydroxylation and methoxylation, leading to the formation of several phenolic metabolites, most of which are converted into glucuronic conjugates.

Two phenolic metabolites are biologically active, but to a much lesser extent than Diclofenac.

The total systemic plasma clearance of diclofenac is 263±56 ml/min. The terminal T_1/2 is 1-2 hours.

The T_1/2 of 4 metabolites, including two pharmacologically active ones, is also short and amounts to 1-3 hours.

About 60% of the drug dose is excreted by the kidneys in the form of glucuronic conjugates of the unchanged substance, as well as in the form of metabolites, most of which are also glucuronic conjugates.

Less than 1% of diclofenac is excreted unchanged. The remaining part of the dose is excreted in the form of metabolites with bile.

The concentration of diclofenac in the blood plasma linearly depends on the applied dose.

Indications

Inflammatory and degenerative diseases of the musculoskeletal system, including rheumatoid, juvenile, chronic arthritis; ankylosing spondylitis and other spondyloarthropathies; osteoarthritis; gouty arthritis; bursitis, tenosynovitis; pain syndrome from the spine (lumbago, sciatica, ossalgia, neuralgia, myalgia, arthralgia, radiculitis); post-traumatic postoperative pain syndrome accompanied by inflammation (for example, in dentistry and orthopedics). Renal colic, biliary colic. Post-traumatic and postoperative pain syndrome accompanied by inflammation. Severe migraine attacks.

ICD codes

Dosage Regimen

Solution

Administered deep intramuscularly. A single dose is 75 mg. If necessary, repeated administration is possible, but not earlier than after 12 hours.

The duration of use is no more than 2 days; if necessary, further switch to oral or rectal administration of diclofenac.

In severe cases (for example, with colic), as an exception, 2 injections of 75 mg each can be given, with an interval of several hours (the second injection should be given in the opposite gluteal region). As an alternative, intramuscular injection once a day (75 mg) can be combined with the intake of diclofenac in other dosage forms (tablets, rectal suppositories), while the total daily dose should not exceed 150 mg.

For migraine attacks, Diclofenac is recommended to be administered as early as possible after the onset of the attack, intramuscularly at a dose of 75 mg, followed by the use of suppositories at a dose of up to 100 mg on the same day, if required. The total daily dose should not exceed 175 mg on the first day.

Tablets

The dose is selected individually, it is recommended to use the minimum effective dose, if possible, with the shortest possible treatment period.

Gel

For external use, the amount of the drug depends on the size of the painful area. A single dose depends on the dosage form used and the age of the patient.

Gel, ointment, spray for external use

For adults and children over 12 years of age, the drug should be applied to the skin over the area of inflammation 3-4 times a day, for children aged 6 to 12 years – up to 2 times a day.

The duration of use depends on the indications and the effectiveness of the treatment. After 2 weeks of using the drug, the patient should consult a doctor.

Transdermal patch

Used in the form of applications on the skin.

For adults, elderly patients and adolescents over 15 years of age, the patch is applied to the skin over the painful area for 24 hours. Only 1 patch is allowed to be used per day.

When treating soft tissue injuries, the patch is used for no more than 14 days, and when treating diseases of muscles and joints – for no more than 21 days, unless otherwise recommended by a doctor.

If there is no improvement in the condition after 7 days and if the well-being worsens, it is necessary to consult a doctor.

Adverse Reactions

From the digestive system: often – abdominal pain, nausea, vomiting, diarrhea, dyspepsia, flatulence, decreased appetite, anorexia, increased activity of aminotransferases in the blood serum; rarely – gastritis, gastrointestinal bleeding, vomiting blood, melena, diarrhea with blood, stomach and intestinal ulcers (with or without bleeding or perforation), hepatitis, jaundice, impaired liver function; very rarely – stomatitis, glossitis, damage to the esophagus, the occurrence of diaphragm-like strictures in the intestine, colitis (nonspecific hemorrhagic colitis, exacerbation of ulcerative colitis or Crohn’s disease), constipation, pancreatitis, fulminant hepatitis, liver necrosis, liver failure.

From the nervous system: often – headache, dizziness; rarely – drowsiness; very rarely – sensory disturbances, including paresthesia, memory disorders, tremor, convulsions, anxiety, acute cerebrovascular accidents, aseptic meningitis; very rarely – disorientation, depression, insomnia, nightmares, irritability, mental disorders.

From the senses: often – vertigo; very rarely – visual disturbances (blurred vision), diplopia, hearing impairment, tinnitus, dysgeusia.

Dermatological reactions: often – skin rash; rarely – urticaria; very rarely – bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), exfoliative dermatitis, itching, hair loss, photosensitivity reactions; purpura, Henoch-Schönlein purpura.

From the genitourinary system: very rarely – acute renal failure, hematuria, proteinuria, tubulointerstitial nephritis, nephrotic syndrome, papillary necrosis.

From the hematopoietic system: very rarely – thrombocytopenia, leukopenia, hemolytic anemia, aplastic anemia, agranulocytosis.

Allergic reactions: rarely – hypersensitivity, anaphylactic/anaphylactoid reactions, including decreased blood pressure and shock; very rarely – angioedema (including facial edema).

From the cardiovascular system: very rarely – palpitations, chest pain, increased blood pressure, vasculitis, heart failure, myocardial infarction. There is evidence of a slight increase in the risk of cardiovascular thrombotic complications (for example, myocardial infarction), especially with long-term use of diclofenac in high doses (daily dose more than 150 mg).

From the respiratory system: rarely – asthma (including shortness of breath); very rarely – pneumonitis.

General reactions and disorders at the injection site: often – pain, induration at the injection site; rarely – edema, necrosis at the injection site.

Contraindications

Hypersensitivity to diclofenac and excipients of the drug used; “aspirin triad” (attacks of bronchial asthma, urticaria and acute rhinitis when taking acetylsalicylic acid or other NSAIDs); erosive and ulcerative lesions of the gastrointestinal tract in the acute phase; severe renal failure (creatinine clearance <30 ml/min), progressive kidney disease; severe hepatic failure, active liver disease; clinically confirmed coronary artery disease, diseases of peripheral arteries and cerebral vessels, uncontrolled arterial hypertension, decompensated heart failure; cerebrovascular bleeding; hemostasis disorders; early postoperative period after coronary artery bypass grafting; confirmed hyperkalemia; third trimester of pregnancy; breastfeeding; childhood and adolescence under 18 years.

With caution

Suspicion of gastrointestinal disease; history of gastrointestinal bleeding and ulcer perforation (especially in elderly patients), Helicobacter pylori infection, ulcerative colitis, Crohn’s disease; mild and moderate liver dysfunction, hepatic porphyria (Diclofenac may provoke porphyria attacks); in patients with gastrointestinal anastomosis (risk of anastomosis integrity impairment), after gastrointestinal surgery (it is required to monitor the condition of patients); in patients with bronchial asthma, seasonal allergic rhinitis, edema of the nasal mucosa (including with polyps in the nasal cavity), COPD, chronic infectious diseases of the respiratory tract (especially those associated with allergic rhinitis-like symptoms); cardiovascular diseases (including coronary artery disease, cerebrovascular diseases, compensated heart failure, peripheral vascular diseases); impaired renal function, including chronic renal failure (creatinine clearance 30-60 ml/min); dyslipidemia/hyperlipidemia; diabetes mellitus; arterial hypertension; significant decrease in circulating blood volume of any etiology (for example, in the periods before and after major surgical interventions); risk of thrombosis (including myocardial infarction and stroke); systemic connective tissue diseases; elderly patients, especially debilitated or with low body weight (Diclofenac should be used in the minimum effective dose); simultaneous use with drugs that increase the risk of gastrointestinal bleeding, including systemic corticosteroids (including prednisolone), anticoagulants (including warfarin), antiplatelet agents (including clopidogrel, acetylsalicylic acid), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline); simultaneous treatment with diuretics or other drugs that can impair renal function; when treating smoking patients or patients who abuse alcohol.

Use in Pregnancy and Lactation

There is insufficient data on the safety of diclofenac use in pregnant women. Therefore, prescription in the first and second trimesters of pregnancy is possible only in cases where the expected benefit to the mother outweighs the potential risk to the fetus. Diclofenac (like other prostaglandin synthesis inhibitors) is contraindicated in the third trimester of pregnancy (possible suppression of uterine contractility and premature closure of the arterial duct in the fetus).

Contraindicated for use during breastfeeding.

Use in Hepatic Impairment

Contraindications: severe hepatic failure, active liver disease.

Use in Renal Impairment

Contraindications: severe renal failure (creatinine clearance <30 ml/min), progressive kidney disease.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Use with particular caution in elderly patients.

Special Precautions

During treatment, systematic monitoring of liver and kidney function, and peripheral blood picture is necessary.

The anti-inflammatory effect of diclofenac may complicate the diagnosis of infectious processes.

During treatment with systemic dosage forms, alcohol consumption is not recommended.

Effect on the ability to drive vehicles and mechanisms

During treatment, a decrease in the speed of psychomotor reactions is possible. If visual clarity deteriorates after using eye drops, you should not drive a car or engage in other potentially hazardous activities.

Drug Interactions

Potent CYP2C9 inhibitors – when diclofenac and potent CYP2C9 inhibitors (such as voriconazole) are co-administered, an increase in the serum concentration of diclofenac and an enhancement of the systemic effect caused by inhibition of diclofenac metabolism are possible.

Lithium, digoxin – an increase in the plasma concentration of lithium and digoxin is possible. Monitoring of serum lithium and digoxin concentrations is recommended.

Diuretic and antihypertensive agents – when used concomitantly with diuretics and antihypertensive drugs (for example, beta-blockers, ACE inhibitors), Diclofenac may reduce their antihypertensive effect.

Cyclosporine – the effect of diclofenac on prostaglandin activity in the kidneys may enhance the nephrotoxicity of cyclosporine.

Drugs that can cause hyperkalemia – concomitant use of diclofenac with potassium-sparing diuretics, cyclosporine, tacrolimus and trimethoprim may lead to an increase in plasma potassium levels (in case of such a combination, this indicator should be monitored frequently).

Quinolone-derived antibacterial agents – there are isolated reports of seizures in patients receiving quinolone derivatives and Diclofenac simultaneously.

NSAIDs and Corticosteroids – with the simultaneous systemic application of diclofenac and other systemic NSAIDs or corticosteroids, the frequency of adverse events (in particular, from the gastrointestinal tract) may increase.

Anticoagulants and Antiplatelet Agents – an increased risk of bleeding cannot be excluded with the simultaneous use of diclofenac and drugs of the specified groups.

Selective Serotonin Reuptake Inhibitors – an increased risk of gastrointestinal bleeding is possible.

Hypoglycemic Drugs – cases of both hypoglycemia and hyperglycemia cannot be excluded, which necessitated a change in the dose of hypoglycemic drugs during the use of diclofenac.

Methotrexate – if diclofenac is used within 24 hours before or within 24 hours after taking methotrexate, an increase in the concentration of methotrexate in the blood and an increase in its toxic effect are possible.

Phenytoin – an enhancement of the effect of phenytoin is possible.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.